Antidepressant azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans

ABSTRACT

Compounds of the Formula:  
                 
 
     are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is continuation-in-part application of U.S.application Ser. No. 60/410,168, filed Sep. 12, 2002, the disclosure ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to antidepressant azaheterocyclylmethylderivatives of heterocycle-fused benzodioxans, to processes forpreparing them, methods of using them and to pharmaceutical compositionscontaining them.

BACKGROUND OF THE INVENTION

[0003] Major depression is a serious health problem affecting more than5% of the population, with a lifetime prevalence of 15-20%.

[0004] Selective serotonin reuptake inhibitors have produced success intreating depression and related illnesses and have become among the mostprescribed drugs. They nonetheless have a slow onset of action, oftentaking several weeks to produce their full therapeutic effect.Furthermore, they are effective in less than two-thirds of patients.

[0005] Serotonin selective reuptake inhibitors (SSRIs) are well knownfor the treatment of depression and other conditions. SSRIs work byblocking the neuronal reuptake of serotonin, thereby increasing theconcentration of serotonin in the synaptic space, and thus increasingthe activation of postsynaptic serotonin receptors.

[0006] However, although a single dose of an SSRI can inhibit theneuronal serotonin transporter which would be expected to increasesynaptic serotonin, long-term treatment is required before clinicalimprovement is achieved.

[0007] It has been suggested that the SSRIs increase the serotoninlevels in the vicinity of the serotonergic cell bodies and that theexcess serotonin activates somatodendritic autoreceptors, 5HT_(1A)receptors, causing a decrease in serotonin release in major forebrainareas. This negative feedback limits the increment of synaptic serotoninthat can be induced by antidepressants.

[0008] A 5HT_(1A) antagonist would limit the negative feedback andshould improve the efficacy of the serotonin reuptake mechanism (Perez,V., et al., The Lancet, 349:1594-1597 (1997)). Such a combinationtherapy would be expected to speed up the effect of the serotoninreuptake inhibitor.

[0009] Thus, it is highly desirable to provide improved compounds whichboth inhibit serotonin reuptake and which are antagonists of the5HT_(1A) receptor.

DESCRIPTION OF THE INVENTION

[0010] In accordance with this invention, there is provided a group ofnovel compounds of Formula I:

[0011] wherein

[0012] Q is

[0013] R¹, R² and R³ are, independently, hydrogen, hydroxy, halo, cyano,carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atomsor alkanesulfonamido of 1 to 6 carbon atoms;

[0014] X and Y are, independently, hydrogen, hydroxy, halo, cyano,carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms,alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atomsor alkanesulfonamido of 1 to 6 carbon atoms, or X and Y, taken together,form —N═C(R⁴)—C(R⁵)═N—, —N═C(R⁴)—C(R⁶)═CH—, —N═C(R⁴)—N═CH—, —N═C(R⁴)—O—,—NH—C(R⁷)═N— or —NH—C(R⁸)═CH—;

[0015] R⁴ and R⁵ are, independently, hydrogen, halo, amino, mono- ordi-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkylof 1 to 6 carbon atoms;

[0016] R⁶ is hydrogen or alkyl of 1 to 6 carbon atoms;

[0017] R⁷ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino,mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atomsor alkyl of 1 to 6 carbon atoms;

[0018] R⁸ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or alkylof 1 to 6 carbon atoms;

[0019] Z is O, S, or NR⁹, in which R⁹ is hydrogen or alkyl of 1 to 6carbon atoms;

[0020] n is an integer 0, 1, or 2;

[0021] m is an integer from 1 to 4, provided that m+n≦4 and that whenm=n=2, and Q is b then X and Y are not NH—C(R⁸)═CH—; and

[0022] p is an integer from 1 to 3, provided that p+n is 2 or 3;

[0023] or a pharmaceutically acceptable salt thereof.

[0024] R¹ is preferably hydrogen, halo, cyano, trifluoromethyl, alkyl of1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms. More preferably,R¹ is hydrogen, halo or alkoxy of 1 to 6 carbon atoms. In still morepreferred embodiments of the present invention, R¹ is hydrogen.

[0025] R² and R³ are preferably independently selected from hydrogen,hydroxy, halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, oralkoxy of 1 to 6 carbon atoms. In still more preferred embodiments ofthe present invention R² and R³ are preferably independently selectedfrom hydrogen, cyano or halogen.

[0026] R⁴ and R⁵ are preferably independently hydrogen, amino or alkylof 1 to 6 carbon atoms. More preferably, R⁴ and R⁵ are independentlyhydrogen or alkyl of 1 to 3 carbon atoms.

[0027] R⁷ and R⁸ are preferably independently selected from hydrogen,trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms. Morepreferably, R⁷ and R⁸ are independently hydrogen, trifluoromethyl oralkyl of 1 to 3 carbon atoms.

[0028] R⁶ is preferably hydrogen or alkyl of 1 to 3 carbon atoms, Z ispreferably NR⁹ in which R⁹ is hydrogen or alkyl of 1 to 3 carbon atoms,n is preferably 0 or 1, m is preferably 1 to 3 and p is preferably 1 or2.

[0029] In other preferred embodiments of the invention are providedcompounds of Formula Ia.

[0030] wherein R¹, R⁴, R⁶, Q, m, n and p are as described above.

[0031] This invention relates to both the R and S stereoisomers of thebenzodioxan methylamines as well as to mixtures of the R and Sstereoisomers. Throughout this application, the name of the product ofthis invention, where the absolute configuration of the compounds of theinvention is not indicated, is intended to embrace the individual R andS enantiomers as well as mixtures of the two. In some embodiments of thepresent invention the S configuration of the2-aminomethyl-2,3-dihydro-1,4-benzodioxan moiety is preferred. Certainof the compounds of this invention (i.e., m does not equal n) containtwo stereogenic centers and thus may exist as diastereomers. Thisinvention relates to both diastereomers, as well as to mixtures ofdiastereomers For certain of the compounds of the invention (i.e., X andY form an imidazole), tautomeric forms may exist. This application thusencompasses all tautomeric forms of compounds of the present invention.

[0032] Where a stereoisomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. “Substantially free,” asused herein, means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments, thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,New York, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

[0033] “Alkyl,” as used herein, refers to an aliphatic hydrocarbon chainand includes straight and branched chains such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers toalkyl having 1 to 3 carbon atoms.

[0034] “Alkanamido,” as used herein, refers to the group R—C(═O)—NH—where R is an alkyl group of 1 to 5 carbon atoms.

[0035] “Alkanoyl,” as used herein, refers to the group R—C(═O)— where Ris an alkyl group of 1 to 5 carbon atoms.

[0036] “Alkanoyloxy,” as used herein, refers to the group R—C(═O)—O—where R is an alkyl group of 1 to 5 carbon atoms.

[0037] “Alkanesulfonamido,” as used herein, refers to the groupR—S(O)₂—NH— where R is an alkyl group of 1 to 6 carbon atoms.

[0038] “Alkanesulfonyl,” as used herein, refers to the group R—S(Q)₂—where R is an alkyl group of 1 to 6 carbon atoms.

[0039] “Alkoxy,” as used herein, refers to the group R—O— where R is analkyl group of 1 to 6 carbon atoms.

[0040] “Carboxamido,” as used herein, refers to the group NH₂—C(═O)—.

[0041] “Carboalkoxy,” as used herein refers to the group R—O—C(═O)—where R is an alkyl group of 1 to 5 carbon atoms.

[0042] “Halogen” (or “halo”), as used herein, refers to chlorine,bromine, fluorine, and iodine.

[0043] Pharmaceutically acceptable salts are those derived from suchorganic and inorganic acids as: acetic, lactic, citric, cinnamic,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic,propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic,salicylic, benzoic, and similarly known acceptable acids.

[0044] Specific examples of compounds of Formula I are:

[0045]2-[3-(5-Fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0046]2-[3-(5-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0047]2-[3-(6-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0048]2-[3-(1H-Indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0049]2-[3-(5-Fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0050]2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

[0051]2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

[0052]1-[(1-{[8-Methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)piperidin-4-yl]-1H-indole-6-carbonitrile;

[0053]2-[3-(6-Fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0054]2-{3-[2-(6-Fluoro-indol-1-yl)-ethyl]-azetidin-1-ylmethyl}-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

[0055]1-{2-[1-(8-Methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetinin-3-yl]-ethyl}-1H-indole-6-carbonitrile;and

[0056]8-Methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

[0057] Compounds of the present invention are suitably prepared inaccordance with the following general description and specific examples.Variables used are as defined for Formula I, unless otherwise noted.Specifically (Scheme 1), the appropriately substituted azaheterocycle(2) is combined with a suitably substituted benzodioxan methyltosylateor bromide (1) in a solvent such as dimethyl sulfoxide and heated to atemperature of 70-100° C. for several hours as illustrated below.Alternatively, the appropriately substituted azaheterocycle may beacylated with a suitably substituted benzodioxan carboxylic acidchloride, and the resulting amide reduced to the amine with a suitablereducing agent such as lithium aluminum hydride or borane/THF. Theazaheterocycle may also be combined with a suitably substitutedbenzodioxan carboxaldehyde in the presence of a reducing agent such assodium cyanoborohydride.

[0058] The benzodioxan methyltosylates and halides (1) are knowncompounds or they may be prepared from the appropriately substitutedsalicylaldehydes by the method (a) described in Scheme 2 below. Thesalicylaldehyde (3) is alkylated with an epihalohydrin or glycidylarylsulfonate in the presence of a suitable base. The aldehyde moiety isthen converted to a phenol by a Baeyer-Villager procedure andcyclization to the benzodioxan methanol (5) effected by treatment with abase such as potassium carbonate. The alcohol is elaborated to atosylate (1) by treatment with p-toluenesulfonyl chloride and a tertiaryamine base or to a bromide by treatment. Alternatively (b), thesubstituted salicylaldehyde (6) may be protected with a suitableprotecting group such as benzyl and the aldehyde (7) converted to aphenol (8) as described above. Following elaboration of the phenol tothe glycidyl ether (9) by treatment with an epihalohydrin or glycidylarylsulfonate, deprotection and cyclization are effected in a singlestep via a transfer hydrogenation in the presence of sodium bicarbonate.The bromide or tosylate is prepared as described above. Or thebenzodioxan methylbromide may be prepared from a suitably substitutedguaiacol (10) by procedure (c) shown above. The guiacol is alkylatedwith a glycidyl arylsulfonate or an epihalohydrin as described above.The methyl ether (11) is then cleaved by treatment with 48% HBr; thisalso converts the epoxide to a bromohydrin (12). Cyclization directly tothe benzodioxan methylbromide (1) is effected by the Mitsonobuprocedure.

[0059] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines ofthe invention in which R⁴ is H are alternatively prepared as illustratedin Scheme 3 below. Specifically, the appropriately substitutednitroguaiacol (13) is alkylated with allyl bromide in the presence of asuitable base such as sodium hydride and then demethylated by a reagentsuch as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenol (15) isthen alkylated with glycidyl tosylate or an epihalohydrin in thepresence of a base such as sodium hydride and heated in a high boilingsolvent such as mesitylene or xylene to effect both rearrangement of theallyl group and cyclization of the dioxan ring. The resulting primaryalcohol (17) is converted to the tosylate by reaction withp-toluenesulfonyl chloride in the presence of a tertiary amine orpyridine, or alternatively to a halide by reaction with carbontetrabromide or carbon tetrachloride in combination withtriphenylphosphine. The allyl side chain is then isomerized by treatmentwith catalytic bis-acetonitrile palladium (II) chloride in refluxingmethylene chloride or benzene. Allylic oxidation of 18 with seleniumdioxide in refluxing dioxane/water gives the o-nitrocinnamaldehyde,which upon reduction with iron in acetic acid cyclizes to the2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (19) or halide.Replacement of the tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

[0060] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines ofthe invention in which R⁴ is alkyl may be prepared from the nitro olefindescribed above in the following manner (Scheme 4). The rearrangedolefin (18) is treated sequentially with ozone and a tertiary amine orwith osmium tetroxide and sodium periodate to give theo-nitrobenzaldehyde (20). Condensation with the appropriatetriphenylphosphorylidene ketone under Wittig conditions gives theo-nitrocinnamyl ketone (21), which upon reduction by iron in aceticacid, cyclizes to the corresponding2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (22).Replacement of the tosylate with the appropriately substitutedazaheterocycles as above gives the title compounds of the invention.Substitution of trimethyl phosphonoacetate for thetriphenylphosphorylidene ketone in the Wittig procedure above, followedby reduction of the nitro group with tin (II) chloride and cyclizationin acid gives the compounds of the invention in which R⁴ is hydroxy.Treatment of the hydroxy derivative with an inorganic acid chloride suchas phosphoryl chloride or bromide gives the compounds of the inventionin which R⁴ is halo. Substitution of diethyl cyanomethylphosphonate forthe triphenylphosphorylidene ketone in the Wittig procedure above,followed by reduction of the nitro group with tin (II) chloride andcyclization in acid gives the compounds of the invention in which R⁴ isamino.

[0061] Compounds of the invention in which R¹ is attached to position 6of the 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines may bealternatively prepared by a variation of the Skraup quinoline synthesisaccording to Scheme 5 below. The appropriately substituted benzodioxanmethyltosylate (23) is nitrated under standard conditions with nitricacid in a solvent such as dichloroethane and the resulting nitrocompound (24) reduced by treatment with hydrogen in the presence of acatalyst such as platinum on sulfide carbon. Treatment of the resultinganiline (25) with acrolein in the presence of hydrogen chloride and anoxidant such as p-chloranil or naphthoquinone gives the corresponding2,3-dihydro-1,4-dioxino[2,3-f]quinoline (26). Replacement of thetosylate with the appropriately substituted azaheterocycles as abovegives the title compounds of the invention.

[0062] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines ofthe invention are prepared as illustrated below (Scheme 6). Theo-nitrobenzaldehyde (20) described above is converted to the oxime (27)by treatment with hydroxylamine hydrochloride in the presence of asuitable base such as sodium acetate and the nitro group reduced to theamine by hydrogenation over palladium on carbon. Cyclization to thequinazoline N-oxide is effected by treatment at reflux with theappropriate ortho ester according to the method of Ostrowski(Heterocycles, vol. 43, No. 2, p. 389, 1996). The quinazoline N-oxidemay be reduced to the quinazoline (28) by a suitable reducing agent suchas hydrogen over Raney-nickel. Alternatively, an extended period ofreflux in the ortho ester gives the reduced quinazoline directly via adisproportionation reaction and the2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate or halide maybe isolated by column chromatography. Replacement of the tosylate orhalide with the appropriately substituted azaheterocycles in some highboiling solvent such as dimethyl sulfoxide gives the title compounds ofthe invention.

[0063] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines ofthe invention may be alternatively prepared from the rearranged olefindescribed above by the method outlined in Scheme 7 below. The nitroolefin (18) is first reduced to the aniline by treatment with a suitablereducing agent such as stannous chloride dihydrate in refuxing ethylacetate and the resulting amine acylated with the appropriate acylhalide or anhydride. The olefin (29) is then converted to the aldehyde(30) by cleavage with catalytic osmium tetroxide in the presence ofexcess sodium periodate. Cyclization directly to the2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate (28) orhalide is effected by treatment of the amido aldehyde (30) with ammoniaand replacement of the tosylate or halide with the appropriatelysubstituted azaheterocycles in some high boiling solvent such asdimethyl sulfoxide as described above gives the title compounds of theinvention.

[0064] The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines ofthe invention are prepared as illustrated in Scheme 8 below. Theo-nitrobenzaldehyde (20) described above is oxidized to theo-nitrobenzoic acid (31) by a suitable oxidant such as chromium trioxide(Jones' oxidation) or sodium chlorite and the acid converted to theo-nitroaniline (32) with diphenylphosphoryl azide (DPPA) in the presenceof a tertiary base such as diisopropylethylamine. Reduction of theresulting nitroaniline to the diamine (33) with hydrogen and palladiumon carbon and cyclization by treatment with the appropriate dicarbonylcompound (for example, glyoxal, 2,3-butanedione, 3,4-hexanedione) givesthe 2,3-dihydro-1,4-dioxino[2,3-f]quinoxaline-2-methyltosylate (34) orhalide. Replacement of the tosylate or halide with the appropriatelysubstituted azaheterocycles in some high boiling solvent such asdimethyl sulfoxide gives the title compounds of the invention.

[0065] The o-nitrobenzaldehyde (20) used in the chemistry describedabove may be alternatively prepared as shown in scheme 9 below. Theappropriate mono-allylated catechol (35) is elaborated with glycidyltosylate as described above and rearranged in refluxing mesitylene.Cyclization to the benzodioxan methanol (37) is effected by treatmentwith sodium bicarbonate in ethanol and the alcohol is converted to thetosylate (38) or halide as described above. After rearrangement of thedouble bond by treatment with catalytic bis-acetonitrile palladium (II)chloride in refluxing methylene chloride and cleavage with ozone orosmium tetroxide/sodium periodate as described above, the resultingaldehyde (39) is regioselectively nitrated with a combination of nitricacid and tin (IV) chloride.

[0066] The7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines of theinvention are prepared as illustrated in Scheme 10 below. The amidoolefin (29) described in Scheme 7 is cleaved to the correspondingo-amidobenzaldehyde (30) by treatment with catalytic osmium tetroxide inthe presence of sodium periodate. The aldehyde is converted to thephenol (40) by treatment with meta-chloroperoxybenzoic acid in aBaeyer-Villager reaction and cyclization to the7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (41) is effected bytreatment at reflux with an appropriate dehydrating agent such as anortho ester or an acid catalyst such as p-toluenesulfonic acid.Replacement of the tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

[0067] Alternatively (Scheme 11), the nitro olefin (18) may be reducedwith tin (II) chloride as described in Scheme 7 above and protected witha suitable protecting group such as carbobenzoxy (Cbz) before the olefinis cleaved to the aldehyde (43) by treatment with osmiumtetroxide/sodium periodate and the aldehyde converted to a phenol (44)by the Baeyer-Villager procedure. Deprotection by treatment withhydrogen over palladium on carbon gives the o-aminophenol, (45) which iscyclized to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (41) bytreatment with the appropriate ortho ester, carboxylic acid oranhydride. Treatment of the o-aminophenol with cyanogen bromide orchloride or a suitably substituted carbamoyl chloride leads to compoundsof the invention in which R⁴ is amino. Treatment of the o-aminophenolwith carbonyl diimidazole gives the oxazolone that leads to compounds ofthe invention in which R⁴ is halo via treatment with an inorganicanhydride such as phosphoryl chloride or bromide. Replacement of thetosylate with the appropriately substituted azaheterocycles as abovegives the title compounds of the invention.

[0068] Compounds of the invention in which R¹ is hydrogen and R⁴ isalkyl are most conveniently prepared according to scheme 12 below. Theappropriate 2′,3′,4′-trihydroxyacylphenone (46) is regioselectivelyalkylated with glycidyl tosylate or an epihalohydrin in the presence ofa base such as sodium carbonate to give the corresponding7-acyl-8-hydroxybenzodioxan-2-methanol (47). Following conversion of theketone to the oxime (48) by reaction with hydroxylamine hydrochlorideand sodium acetate, cyclization to the oxazole (49) is effected bytreatment with phosphoryl chloride in the appropriate dimethylalkanoicacid amide. The resulting7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol isconverted to the tosylate (50) by treatment with p-toluenesulfonylchloride in pyridine and combined with the appropriate azaheterocyclesas described above to give the title compounds of the invention.

[0069] The 7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenesof the invention are prepared as illustrated in Scheme 13 below. Thediamine 33 described in Scheme 8 is cyclized by treatment at reflux withthe appropriate carboxylic acid to give the imidazole (51). Refluxingthe diamine dihydrochloride in higher boiling carboxylic acidsoccasionally causes replacement of a tosylate group with a chloride.Replacement of the tosylate or halide with the appropriately substitutedpiperidine in some high boiling solvent such as dimethyl sulfoxide givesthe 7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of theinvention in which R⁷ is hydrogen, perfluoroalkyl, or alkyl. Treatmentof the diamine described above with cyanogen bromide or chloride or asuitably substituted carbamoyl chloride leads to compounds of theinvention in which R⁷ is amino. Treatment of the diamine with carbonyldiimidazole gives the imidazolone that leads to compounds of theinvention in which R⁷ is halo via treatment with an inorganic anhydridesuch as phosphoryl chloride or bromide. Replacement of the tosylate withthe appropriately substituted azaheterocycles as above gives the titlecompounds of the invention.

[0070] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the inventionare prepared as illustrated in Scheme 14 below. Specifically, theprimary alcohol (17) from the Claisen rearrangement described in Scheme3 is converted to the tosylate (52) by reaction with p-toluenesulfonylchloride in the presence of a tertiary amine or pyridine, oralternatively to a halide by reaction with carbon tetrabromide or carbontetrachloride in combination with triphenylphosphine. The allyl sidechain is then cleaved to the aldehyde (53) by treatment with ozone atlow temperature, followed by work-up with a tertiary base such asdiisopropylethylamine or triethylamine, or by treatment with catalyticosmium tetroxide and sodium periodate. Reduction of the nitro group withhydrogen over platinum oxide leads directly to formation of the indole(54) in which R⁸ is hydrogen. Alternatively, the aldehyde may be treatedwith an appropriate alkyl Grignard reagent or with trifluoromethyltrimethylsilane in the presence of cesium fluoride, then oxidized to aketone with a suitable oxidant such as pyridinium chlorochromate (PCC)or the Swern reagent and reduced with hydrogen over platinum oxide togive the indoles in which R⁸ is alkyl or trifluoromethyl. Replacement ofthe tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

[0071] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the inventionmay alternatively be prepared from nitroaldehyde 20 by the followingprocedure (Scheme 15). The o-nitrobenzaldehyde (20) iscondensed with theappropriate nitroalkane in the presence of a suitable base catalyst toyield the corresponding o,β-dinitrostyrene (55). Reduction of both nitrogroups with hydrogen over palladium on carbon is accompanied bycyclization to form the indole (56). Replacement of the tosylate withthe appropriately substituted azaheterocycles as above gives the titlecompounds of the invention.

[0072] The compounds of the invention may be resolved into theirenantiomers by conventional methods or, preferably, the individualenantiomers may be prepared directly by substitution of(2R)-(−)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the Sbenzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonateor tosylate (for the R enantiomer) in place of epihalohydrin or racemicglycidyl tosylate in the procedures above.

[0073] In yet another method, the heterocycle-fused benzodioxans of thepresent invention may be prepared in accordance with Scheme 16. Thesynthesis of compound I is comprised of steps that begin withhalogenation of 57 where R′ is alkyl of 1-6 carbon atoms, with reagentssuch as N-halosuccinimide in acetonitrile to give 58 (where Hal ishalogen such as Br, Cl or I). Deprotecting 58 with Lewis acids such asboron tribromide, boron trichloride, aluminum trichloride, ferricchloride, or trimethylsilyl iodide in a suitable solvent such asmethylene chloride, or with strong protic acids such as HBr and HClgives the salt 59. Free base 59 may be obtained by neutralization withan Amberlyst A-21 resin slurry in polar solvents such as ethanol ormethanol.

[0074] Alkylation of 59, either as the free base or as the salt, withbenzyl or substituted benzyl protected glycidyl ethers

[0075] where R″ is benzyl, substituted benzyl such as 4-bromobenzyl,3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxybenzyl) insuitable polar solvents such as DMSO, DMF, or DMA in the presence ofbases such as sodium carbonate, potassium carbonate, or triethylaminegives 60. 60 was then cyclized using palladium catalysts such astris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate with ligandsfrom the group consisting of (±) BINAP and separate enantiomers thereof,(±) Tol-BINAP and separate enantiomers thereof;1-1′-bis(diphenylphosphino) ferrocene,1,3-bis(diphenylphosphino)propane, and 1,2 bis(diphenyl-phosphino)ethanein the presence of bases such as NaH, LiH, KH, potassium carbonate,sodium carbonate, titanium carbonate, cesium carbonate, potassiumt-butoxide or potassium phosphate tribasic in suitable solvent such astoluene, or alternatively, with copper catalyst such as copper iodide inthe presence of bases such NaH, LiH, KH in a suitable solvent such astoluene to afford 61.

[0076] Deprotection of quinoline 61 with Lewis acids such as borontribromide, boron trichloride, aluminum trichloride, ferric chloride,trimethylsilyl iodide in a suitable solvent such as methylene chloride,or with strong protic acids such as HBr and HCl or under reductivecleavage conditions using Pd catalyst and hydrogen transfer reagentssuch as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formategives the heterocycle-fused benzodioxanmethanol 62. The hydroxyl moietyof 62 can be activated with an aryl- or alkylsulfonyl chloride such asp-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfonylchloride in the presence of bases such as triethylamine or pyridine insuitable solvents such as methylene chloride, THF, or toluene to afford65 where R′″ is a sulfonate such as ptoluenesulfonate, methanesulfonate,2-, 3-, or 4-nitrobenzenesulfonate, or 2- or 4-bromobenzenesulfonate.The final coupling of 63 with azaheterocycles appropriate to theinvention, in the presence of bases such as Huinig's base(diisopropylethylamine), potassium carbonate, or sodium carbonate inpolar solvents such as THF, dioxane, DMSO, DMF, or DMA affords thecompounds of the invention I.

[0077] The phenols, guaiacols, catechols,2′,3′,4′-trihydroxyacylphenones and benzodioxan methyltosylatesappropriate to the above chemistry are known compounds or can beprepared by one schooled in the art. The azaheterocycles are knowncompounds or they can readily be prepared by one schooled in the artusing the procedures outlined by Baker et al. in WO 94/02477, Gil et.al. In WO 94/24125 or Arora et. al. in WO 00/38677. The azaheterocyclesin which Q is a) and m, n and p are 1 may alternatively be preparedaccording to the method outlined in Scheme 17. The suitably protectedazetidinone (64) is converted to the homologous aldehyde (66) by a twostep procedure involving Wittig reaction of 64 with the betainegenerated from (methoxymethyl)triphenylphosphonium chloride and sodiumhydride, followed by hydrolysis of the resulting enol ether (65) withaqueous acid. The aldehyde (66) is reacted with a suitably substitutedindole under the influence of a base such as sodium hydroxide to givethe condensation product (67). Reduction with triethylsilane, followedby deprotection by transfer hydrogenation gives theindolemethylazetidine (68) useful for the preparation of certain of thecompounds of the invention.

[0078] The azaheterocycles in which Q is b) may alternatively beprepared according to the method outlined in Scheme 18. The suitablyprotected (P represents a protecting group such as carbobenzyloxy,t-butoxycarbonyl, benzhydryl, benzyl, etc.) heterocyclylalkyl halide,tosylate or methanesulfonate 69, in which L represents the leavinggroup, is combined with the appropriately substituted indole and heatedto 40-100° C. in the presence of a base such as sodium hydride in apolar solvent such as N,N-dimethylformamide or methylsulfoxide. Theresulting alkylated indole 70 is then deprotected by the appropriatemeans, for example hydrogenolysis over palladium on carbon forcarbobenzyloxy, benzyl or benzhydryl or treatment with acid fort-butoxycarbonyl, to give the azaheterocycles useful for the preparationof certain of the compounds of the invention.

[0079] A protocol similar to that used by Cheetham et al.(Neuropharmacol. 32:737, 1993) was used to determine the affinity of thecompounds of the invention for the serotonin transporter. The compound'sability to displace ³H-paroxetine from male rat frontal corticalmembranes was determined using a Tom Tech filtration device to separatebound from free ³H-paroxetine and a Wallac 1205 Beta Plate® counter toquantify bound radioactivity. Kj's thus determined for standard clinicalantidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and67.6 nM for zimelidine. A strong correlation has been found between³H-paroxetine binding in rat frontal cortex and ³H-serotonin uptakeinhibition.

[0080] High affinity for the serotonin 5-HT_(1A) receptor wasestablished by testing the claimed compound's ability to displace [³H]8-OHDPAT (dipropylaminotetralin) from the 5-HT_(1A) serotonin receptorfollowing a modification of the procedure of Hall et al., J. Neurochem.44, 1685 (1985) which utilizes CHO cells stably transfected with human5-HT_(1A) receptors. The 5-HT_(1A) affinities for the compounds of theinvention are reported below as Kj's.

[0081] Antagonist activity at 5-HT_(1A) receptors was established byusing a ³⁵S-GTPγS binding assay similar to that used by Lazareno andBirdsall (Br. J. Pharmacol. 109: 1120, 1993), in which the testcompound's ability to affect the binding of ³⁵S-GTPγS to membranescontaining cloned human 5-HT_(1A) receptors was determined. Agonistsproduce an increase in binding whereas antagonists produce no increasebut rather reverse the effects of the standard agonist 8-OHDPAT. Thetest compound's maximum inhibitory effect is represented as the I_(max),while its potency is defined by the IC₅₀.

[0082] The results of the three standard experimental test proceduresdescribed in the preceding three paragraphs were as follows: 5-HT5-HT_(1A) Transporter 5-HT_(1A) Function Affinity Receptor AffinityCompound KI (nM) KI (nM) IC₅₀ (nM) (I_(max)) Example 1 2.50 1.29  59.5(73.7) Example 2 3.30 15.30 552.4 (100) Example 3 3.40 15.12 666.4 (100)Example 4 9.20 0.56  37.2 (76.4) Example 5 16.70 0.72  34.5 (96.3)Example 6 9.55 1.01 241.8 (85.5) Example 7 15.18 1.61 208.1 (81.5)Example 8 6.56 0.60 243.2 (100) Example 9 55.00 0.11 Example 10 1.904.26 342.8 (80.0) Example 11 1.52 2.86 250.9 (85.0) Example 12 1.04 38.6 (89.5)

[0083] Like the antidepressants fluoxetine, paroxetine, and sertraline,the compounds of this invention have the ability to potently block thereuptake of the brain neurotransmitter serotonin. They are thus usefulfor the treatment of diseases commonly treated by the administration ofserotonin selective reuptake inhibitor (SSRI) antidepressants, such asdepression (including but not limited to major depressive disorder,childhood depression and dysthymia), anxiety, panic disorder,post-traumatic stress disorder, premenstrual dysphoric disorder (alsoknown as pre-menstrual syndrome), attention deficit disorder (with andwithout hyperactivity), obsessive compulsive disorders (including butnot limited to trichotillomania), obsessive compulsive spectrumdisorders (including but not limited to autism), social anxietydisorder, generalized anxiety disorder, obesity, eating disorders suchas anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine andalcohol addiction, sexual dysfunction (including but not limited topremature ejaculation), incontinence (including, but not limited tofecal incontinence, urge incontinence, overflow incontinence, passiveincontinence, reflex incontinence, stress urinary incontinence urinaryexertional incontinence and urinary incontinence), and pain (including,but not limited to migraine, chronic back pain, phantom limb pain,neuropathic pain such as diabetic neuropathy, and post herpeticneuropathy) and related illnesses. Moreover, the compounds of thisinvention have potent affinity for and antagonist activity at brain5HT_(1A) serotonin receptors. Recent clinical trials employing drugmixtures (e.g., fluoxetine and pindolol) have demonstrated a more rapidonset of antidepressant efficacy for a treatment combining SSRI activityand 5HT_(1A) antagonism (Blier and Bergeron, 1995; F. Artigas et. al.,1996; M. B. Tome et. al., 1997). The compounds of the invention are thusexceedingly interesting and useful for treating depressive illnesses.

[0084] Thus the present invention provides methods of treating,preventing, inhibiting or alleviating each of the maladies listed abovein a mammal, preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

[0085] Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remington's Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.

[0086] The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substancesthat may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

[0087] Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups, and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers, or osmo-regulators. Suitable examples of liquid carriersfor oral and parenteral administration include water (particularlycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

[0088] Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be administered by, for example, intramuscular,intraperitoneal, or subcutaneous injection. Sterile solutions can alsobe administered intravenously. Oral administration may be either liquidor solid composition form.

[0089] Preferably the pharmaceutical composition is in unit dosage form,e.g. as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

[0090] The amount provided to a patient will vary depending upon what isbeing administered, the purpose of the administration, such asprophylaxis or therapy, and the state of the patient, the manner ofadministration, and the like. In therapeutic applications, compounds ofthe present invention are provided to a patient already suffering from adisease in an amount sufficient to cure or at least partially amelioratethe symptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age, and responsepattern of the patient. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the human.

[0091] Provide, as used herein, means either directly administering acompound or composition of the present invention, or administering aprodrug, derivative or analog that will form an equivalent amount of theactive compound or substance within the body.

[0092] The present invention includes prodrugs of compounds of Formula Iand Ia. “Prodrug,” as used herein, means a compound which is convertiblein vivo by metabolic means (e.g. by hydrolysis) to a compound of FormulaI. Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975).

[0093] The following examples illustrate the production ofrepresentative compounds of this invention.

INTERMEDIATE 1 3-Allyloxy-4-methoxynitrobenzene

[0094] 97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol wasdissolved in one liter of DMF and 1.5 equivalents of allyl bromideadded. The reaction was heated to 65° C. for two hours, after which timemuch of the dark color had discharged and tic (1:1 CH₂Cl₂/hexane)indicated loss of starting material. The solvent was concentrated invacuum and the residue washed with water. The product was isolated byfiltration and dried in a vacuum. This gave 112 g of pale yellow solid.A sample recrystallized from methanol, gave m.p. 93-94° C.

INTERMEDIATE 2 2-Allyloxy-4-nitrophenol

[0095] To one liter of dimethyl sulfoxide was added 750 mL of 2 Naqueous sodium hydroxide and the mixture was heated to 65° C. The paleyellow solid 3-allyloxy-4-methoxynitrobenzene prepared above was addedin portions over a 30-minute period and then the temperature was raisedto 95° C. and maintained for 3 hours, after which time the startingmaterial had been consumed. The mixture was allowed to cool and pouredinto a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude buthomogeneous (by tic 1:1 CH₂Cl₂/hexane) desired product was isolated as alight brown solid by filtration. This material was subsequentlydissolved in 1:1 hexane/methylene chloride and filtered through silicagel to give 68 g of pale yellow solid, which, when recrystallized fromethyl/acetate/hexane, gave m.p. 61-62 ° C. The aqueous mother liquorsfrom the initial crystallization above were extracted with 2 L of ethylacetate. This was dried over sodium sulfate, filtered, and evaporated toa dark oil. Column chromatography on silica with 1:1 CH₂Cl₂/hexane gavean additional 12 g of the title compound as a yellow solid. Elution with2% MeOH in CHCl₃ gave 12 g of a dark oil that slowly crystallized invacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechol.

INTERMEDIATE 3 2-(2-Allyloxy-4-nitrophenoxvmethyl)-oxirane

[0096] 20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two-literflask and washed with 500 mL of hexane. 1 L of DMF was added, followedby 77 g (0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in theprevious step. Addition of the phenol was performed in portions underargon. After stirring the mixture for 30 minutes at room temperatureunder argon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added andthe mixture heated at 70-75° C. under nitrogen overnight. Upon cooling,the DMF was removed in vacuum and replaced with one liter of methylenechloride. This was washed with 500 mL portions of 2 N HCl, saturatedsodium bicarbonate and saturated brine and dried over sodium sulfate.The mixture was filtered, concentrated to an oil in vacuum and columnchromatographed on silica gel using 1:1 hexane/methylene chloride aseluent. This gave 43 g of product contaminated with traces of the twostarting materials, followed by 21 g of pure product as a pale yellowsolid. The impure material was recrystallized from 1.2 L of 10% ethylacetate/hexane to give 34 g of pure (homogeneous on silica gel tic with1:1 hexane/methylene chloride)(R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C.).

[0097] Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N,5.58. Found: C, 57.50; H, 5.21; N, 5.43.

INTERMEDIATE 4(8-Ally-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol

[0098] (R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles)prepared as above was heated at 155° C. in mesitylene for 24 hours undernitrogen. Filtration of the black solid that formed gave 1.5 g of verypolar material. Evaporation of the solvent in vacuum followed by columnchromatography on silica gel with methylene chloride as eluent gave 10 gof recovered starting material and 7.5 g of the desired rearranged(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, whichslowly crystallized on standing in vacuum (m.p. 67° C). The yield basedon recovered starting material is 75%.

[0099] Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N,5.58. Found: C, 57.26; H, 5.20; N, 5.35.

INTERMEDIATE 5 Toluene-4-sulfonic acid8-ally-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester

[0100] 9.55 g (38.0 mmole) of(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol wasdissolved in 465 mL of pyridine, 29.0 g (152 mmole) of p-toluenesulfonylchloride was added and the mixture stirred at room temperature undernitrogen overnight. Water was then added to quench the excess tosylchloride and the solvent was removed in vacuum and replaced withmethylene chloride. This solution was washed with 2 N HCl, withsaturated sodium bicarbonate, and with saturated brine, and dried overmagnesium sulfate. Filtration, evaporation in vacuum and columnchromatography on silica gel with 1:1 hexane/methylene chloride aseluent gave 12.6 g (92%) of toluene-4-sulfonic acid(R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ylmethyl ester, which slowlycrystallized to a tan solid (m.p. 60-62° C.) upon standing.

[0101] Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N,3.45. Found: C, 56.13; H, 4.58; N, 3.44.

INTERMEDIATE 6{7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

[0102] To a solution of 10.0 g (24.0 mmole) of(R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g ofbis(acetonitrile)dichloropalladium (II) and the mixture was refluxedunder nitrogen for 48 hours. The catalyst was then removed by filtrationand the filtrate concentrated in vacuum to a brown oil. Columnchromatography on silica gel with methylene chloride as eluent gave 7.2g of the title compound as a mixture of E and Z isomers. A sample of{(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106°C.) by evaporation of a pure E isomer-containing fraction.

[0103] Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N,3.45. Found: C, 56.12; H, 4.64; N, 3.39.

INTERMEDIATE 7{7-Nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

[0104]{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methyl benzenesulfonate (6.15 g, 15.2 mmole) was dissolved in 180 mLof dioxane. Selenium dioxide (4.20 g, 37.9 mmole) was then added,followed by 0.70 mL of water. The heterogeneous mixture was heated atreflux under nitrogen for 5 hours. Upon cooling, the reaction wasfiltered and concentrated in vacuum to yield a dark yellow solid. Thiswas dissolved in minimal ethyl acetate and column chromatographed onsilica gel using 30% ethyl acetate in hexane as eluent to give 5.75 g ofthe (R)-enantiomer of the title compound as a light yellow solid (m.p.138-140° C.).

[0105] Elemental Analysis for: C₁₉H₁₇NO₈S Calc'd: C, 54.41; H, 4.09; N,3.34. Found: C, 54.10; H, 3.85; N, 3.31.

INTERMEDIATE 8 2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl4-methylbenzenesulfonate

[0106] To a solution of{(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (3.50 g, 8.35 mmole) in 200 mL of aceticacid/ethanol (1:1) was added 2.35 g (42.1 mmole) of iron powder and themixture was heated at reflux under nitrogen for 8 hours. After thereaction was complete, 150 mL of water was added and the mixturefiltered through a pad of celite. The filtrate was neutralized withsaturated sodium bicarbonate and extracted with ethyl acetate. Theextract was dried over magnesium sulfate, filtered, and evaporated invacuum. The residue was column chromatographed on silica gel using agradient elution commencing with 20% ethyl acetate/hexane and endingwith 70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer ofthe title compound as a yellow oil. ¹H-NMR (CDCl₃): doublet 8.8 δ (1 H);doublet 8.2 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); multiplet7.35 δ (1 H); multiplet 7.25 δ (3 H); multiplet 4.6 δ (1 H); multiplet4.3-4.4 δ (3 H); multiplet 4.2 δ (1 H); singlet 2.4 δ (3 H).

INTERMEDIATE 9 (8-Formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate

[0107]{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methyl benzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL ofmethylene chloride was treated with excess ozone at −78° C.Diisopropylethylamine (11.5 mL, 66.0 mmole) was then added dropwise over30 minutes and the mixture allowed to come to room temperature and stirovernight under a nitrogen atmosphere. The mixture was then diluted to600 mL with methylene chloride, washed three times with 100 mL portionsof 2N HCl (aq), twice with 200 mL portions of saturated aqueous sodiumbicarbonate and with 200 mL of saturated brine. The solution was driedover magnesium sulfate, filtered and concentrated in vacuum to a crudebrown oil, which was column chromatographed on silica gel with 10%hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of thetitle compound as a yellow solid. ¹H-NMR (CDCl₃): doublet 7.8 δ (2 H);doublet 7.62 δ (1 H); doublet 7.4 δ (2 H); doublet 7.0 δ (1 H);multiplet 4.4-4.6 δ (2 H); multiplet 4.2 δ (3 H); singlet 2.4 δ (3 H).

INTERMEDIATE 10{7-Nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

[0108] To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin -2-yl]methyl 4-methylbenzenesulfonatein 250 mL of toluene was added 2.90 g (9.10 mmole) of1-triphenylphosphorylidene-2-propanone. The mixture was stirred at roomtemperature under nitrogen for 5 hours, during which time some productprecipitated from solution. The solvent was removed in vacuum and thecrude residue was column chromatographed on silica gel with methylenechloride as eluent to give 3.0 g of the (R)-enantiomer of the titlecompound as a yellow solid. ¹H-NMR (CDCl₃): doublet 7.8 δ (2 H); doublet7.6 δ (1 H); doublet 7.5 δ (2 H); doublet 7.4 δ (2 H); doublet 6.95 δ (1H); doublet 6.6 δ (1 H); multiplet 4.5 δ (1 H); doublet of doublets 4.0δ (1 H); multiplet 4.2 δ (3 H); singlet 2.45 δ (3 H); singlet 2.4 δ (3H).

INTERMEDIATE 11(8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl4-methylbenzenesulfonate

[0109] To a solution of{(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200 mL of aceticacid/ethanol (3:2) was added 2.25 g (40.2 mmole) of iron powder and themixture was heated at reflux under nitrogen for 8 hours. After thereaction was complete, 150 mL of water was added and the mixturefiltered through a pad of celite. The filtrate was neutralized withsaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The extract was dried over magnesium sulfate, filtered, and evaporatedin vacuum. The residue was column chromatographed on silica gel using agradient elution commencing with 20% ethyl acetate/hexane and endingwith 70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of thetitle compound as a yellow oil. ¹H-NMR (CDCl₃): doublet 8.1 δ (1 H);doublet 7.6 δ (2 H); doublet 7.45 δ (1 H); multiplet 7.2 δ (4 H);multiplet 4.6 δ (1 H); multiplet 4.3 δ (3 H); multiplet 4.1 δ (1 H);singlet 2.5 δ (3H); singlet 2.4 δ (3 H).

INTERMEDIATE 12[7-Nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate

[0110] A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid(2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in400 mL of methylene chloride was cooled in a dry ice/isopropanol bathand saturated with ozone. It was then purged with oxygen and 2.6 g (20mmole) of diisopropylethylamine added. The mixture was allowed to cometo room temperature and stirred under nitrogen for 24 hours. It was thenwashed with 300 mL portions of 2 N HCl (aq), water and saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuum togive 3.8 g of the (R)-enantiomer of the title compound as a white solidone-quarter hydrate, m.p. 116-120° C.

[0111] Elemental Analysis for: C₁₈H₁₇NO₈S.0.25 H₂O Calc'd: C, 52.49; H,4.28; N, 3.40. Found: C, 52.33; H, 3.92; N, 3.36.

INTERMEDIATE 13 2,3-Dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl4-methylbenzenesulfonate

[0112] A mixture of 3.75 g (9.2 mmole) of[(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of ethylacetate was treated with 45 psi of hydrogen on a Parr hydrogenationapparatus for 6 hours. The mixture was then filtered through celite andconcentrated in vacuum. The residue was column chromatographed on silicagel with first 10% hexane/methylene chloride, then 1% methanol/methylenechloride and finally 2% methanol/methylene chloride to give 1.50 g ofthe (R)-enantiomer of the title compound as a white solid one-quarterhydrate, m.p. 145° C.

[0113] Elemental Analysis for: C₁₈H₁₇NO₅S.0.25 H₂O Calc'd: C, 59.41; H,4.85; N, 3.85. Found: C, 59.41; H, 4.57; N, 3.72.

INTERMEDIATE 141-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone

[0114] To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0mmole) in DMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole).After 5 minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added,then the heterogeneous mixture was heated to 70° C. for 3 hours. Afterremoval of the solvent in vacuum, the residue was taken into water (800mL) and was then extracted with ethyl acetate (4×300 mL). The combinedorganic layers were dried over magnesium sulfate, filtered and evaporateto dryness in vacuum. The crude brown oil thus obtained was columnchromatographed on silica gel with 40% hexane/ethyl acetate as eluent togive the (S)-enantiomer of the title compound as a yellow oil whichsolidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.

[0115] Elemental Analysis for: C₁₁H₁₂O₅.0.10 H₂O Calc'd: C, 58.46; H,5.44. Found: C, 58.02; H, 5.09.

INTERMEDIATE 151-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime

[0116] A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in1:1 ethanol/pyridine (100 mL) was added to a solution of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone(1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to refluxunder nitrogen for 5 hours. Upon cooling, the solvent was removed andreplaced with ethyl acetate. The solution was then washed with water(200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate,filtered and evaporated in vacuum to give 1.89 g (93%) of the(S)-enantiomer of the title compound as a gray solid, m.p. 162° C. MS(ESI) m/z 240 (M+H)+.

[0117] Elemental Analysis for: C₁₁H₁₃NO₅.0.35 H₂O Calc'd: C, 53.81; H,5.62; N, 5.71. Found: C, 53.51; H, 5.30; N, 5.58.

INTERMEDIATE 16[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol

[0118] 3.03 g (12.6 mmole) of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime was dissolved in a mixture of 1:3N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled inan ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. Thereaction mixture was stirred under nitrogen over a period of 48 hours.It was then added to an ice cold, saturated solution of sodium acetate,extracted with ethyl acetate, dried over magnesium sulfate, filtered andevaporated in vacuum. The resulting crude oil was column chromatographedon silica gel with 60% hexane/ethyl acetate to remove impurities and theproduct eluted with 40% hexane/ethyl acetate. After evaporation of thesolvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the titlecompound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222(M+H)+.

[0119] Elemental Analysis for: C₁₁H₁₁NO₄.0.20 H₂O Calc'd: C, 58.77; H,5.11; N, 6.23. Found: C, 58.93; H, 4.91; N, 6.14.

INTERMEDIATE 17[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl4-methylbenzenesulfonate

[0120] To a solution of[(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol(1.80 g, 8.14 mmole) in methylene chloride (100 mL) was addedp-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooledin an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4mmole) in methylene chloride (20 mL) was then added dropwise, followedby 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution wasallowed to warm to room temperature and was stirred under nitrogenovernight. The reaction was diluted to 500 mL in volume with methylenechloride, then washed with aqueous 2 N HCl (200 mL), with saturatedaqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried overmagnesium sulfate, filtered and evaporated in vacuum to a yellow oil.The crude oil was column chromatographed on silica gel using methylenechloride to remove impurities and 3% methanol/methylene chloride toelute the (R)-enantiomer of the title compound, which becomes a whitesolid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.

[0121] Elemental Analysis for: C₁₈H₁₇NO₆S.0.20 H₂O Calc'd: C, 57.04; H,4.63; N, 3.70. Found: C, 56.75; H, 4.62; N, 3.51.

INTERMEDIATE 18 5-Bromo-6-methoxy-2-methylquinoline

[0122] A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) inacetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wiseaddition of N-bromo-succinimidyl (200 g, 1.12 mol) over a period of 30minutes while maintaining the same temperature. The resulted brownslurry was warmed to ambient temperature and stirred for an additional 6h. The reaction was then quenched by a 10% NaHSO₃ solution (211 mL). Thereaction mixture was concentrated to a volume of 600 mL then slowlypoured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at roomtemperature for 1 h then filtered, washed with water (2×1 L) and driedin a vacuum oven to give 253 g (98.6%) of the title compound as a brownsolid. R_(f)=0.39 (3:7) EtOAc:heptane; ¹H NMR (DMSO) δ 8.30 (d, J=6.5Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H);

[0123] Elemental Analysis for: C₁₁H₁₀NOBr Calc'd: C, 52.40; H, 3.97; N,5.56. Found: C, 52.13; H, 3.94; N, 5.61.

INTERMEDIATE 19 5-Bromo-2-methyl-6-quinolinol

[0124] A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol)in 48% HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in1 hour to give a brown and thick slurry. The slurry was stirred at 0-5°C. for 1 hour then filtered, washed with EtOAc (2×50 mL) and dried in avacuum oven to give 34.9 g (92%) of the hydrobromide of the titlecompound as a brown solid. ¹H NMR (DMSO) δ8.26 (d, J=8.7 Hz, 1H), 7.85(d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64(s, 3H). A slurry of the hydrobromide salt of5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) inMeOH (35 mL) was stirred at room temperature for 3 h. The mixture wasthen filtered and concentrated in vacuo to give 2.5 g (100%) of a yellowsolid. R_(f)=0.36 (1:1) EtOAc:heptane; ¹H NMR (DMSO) δ 8.26 (d, J=8.4Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H).

INTERMEDIATE 20(2S)-1-(Benzyloxy)-3-[(5-bromo-2-methyl-6-quinolinyl)oxy]-2-propanol

[0125] A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol),(R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g,172 mmol) in DMA (200 mL) was heated in a 95-98° C. oil bath for 2 days.The solution was cooled and poured into water (300 mL) while stirring.The tan precipitate formed was filtered, washed with water (100 mL) anddried in a vacuum oven to give 37 g (73%) of the title compound as a tansolid. R_(f)=0.35 (EtOAc); ¹H NMR (DMSO) δ8.31 (d, J=8.8 Hz, 1H), 7.96(d, J=9.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H),7.25-7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m,2H), 4.08-4.15 (m, 1H), 3.61-3.73 (m, 2H), 2.66 (s, 3H); Specificrotation =+6.2° (c=1, CH₃OH);

[0126] Elemental Analysis for: C₂₀H₂₀BrNO₃ Calc'd: C, 59.66; H, 4.97; N,3.48. Found: C, 59.43; H, 4.97; N, 3.55.

INTERMEDIATE 21 (2S)-2[(Benzyloxy)m thyl-8-mthyl-2,3-dihydro[1,4]dioxino [2,3-f]guinolin

[0127] To a mixture of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene(2 L), NaH (10.9 g, 0.45 mol) was added in portions at 30-35° C. over 20min. The reaction mixture was kept at 35° C. for 30 min then heated to110° C. slowly. After 30 min, the reaction was cooled to 60° C.,additional NaH (10.9 g, 0.45 mol) was added. This was warmed to 110° C.for an additional 2 hours then cooled to room temperature beforedropwise addition of water (200 mL). After stirring for 15 min, themixture was filtered through a bed of celite then washed with toluene(3×50 mL) and water (50 mL). The two layers were separated. The organiclayer was extracted with water (100 mL), NH₄OH (100 mL), 25% NaCl (100mL) and concentrated in vacuo to give 387.6 g of the crude product as abrown syrup. The crude product was carried through to the debenzylationstep before purification.

INTERMEDIATE 22[(2R)-8-Methyl-2,3-dihydro[1,4dioxino[2,3-f]quinolin-2-yl]methanol

[0128] To a solution of(2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene(0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated toreflux under N₂ for 18 h then cooled and filtered. The catalyst wasrinsed with methanol and the filtrate was concentrated in vacuo toafford 0.113 g (98%) of the title alcohol as an off-white solid.

[0129]¹H NMR (CD₃OD) δ8.46 (m,1H), 7.47 (m,1H), 7.38-7.31 (m, 2H), 4.40(m,1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H).

INTERMEDIATE 23[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Bromobenzenesulfonate

[0130] A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-flquinolin-2-yl]-methanol(4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylaminopyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) intoluene (40 mL) was stirred at 60° C. for 6 h. The reaction mixture wascooled to room temperature then water (20 mL) was added. After 30 min,the two layers were separated. The organic layer was extracted with 8%NaHCO₃ (20 mL) and H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The solid obtained was dissolved in isopropylalcohol (50 mL) and toluene (10 mL) at 80° C., cooled to roomtemperature over 1 h then filtered, washed with (5:1) IPA: toluene (2×5mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the titlecompound as an off-white solid. ¹³C NMR (CDCl₃) δ157.9, 144.3, 138.1,134.7, 132.9, 129.7, 129.6, 129.0, 122.4, 121.7, 121.3, 118.8, 70.7,67.6, 64.5, 25.4

INTERMEDIATE 24 1-Benzhydryl-azetiin-3-one

[0131] Triethylamine (11.6 ml, 42 mmol) was added to a solution of1-benzhydryl-azetidin-3-ol (2.0 g, 4.2 mmol) in dimethylsulfoxide (60mL) at room temperature. The resulting mixture was cooled to 10° C.,then pyridine sulfur trioxide (8.64 g, 33.6 mmol) in dimethylsulfoxidewas introduced. The mixture was stirred at 10° C. for 1 hour and thenfor 2 hours at room temperature. The reaction mixture was poured intowater (100 mL) and extracted with methylene chloride (3×100 mL). Theorganic layer was washed with water (3×150 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The crude oilwas column chromatographed on silica gel (30% ethyl acetate-hexane). Theproduct-containing fractions were concentrated under vacuum to give 1.7g (86%) of the title compound as a yellow solid, m.p. 52-54° C.

INTERMEDIATE 25 1-B nzhydryl-3-m thoxymethyl ne-az tidine

[0132] To a suspension of sodium hydride (60% mineral oil dispersion,0.10 g, 2.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added(methyoxymethyl)triphenylphosphonium chloride (0.80 g, 2.3 mmol) at 0°C. The mixture was stirred at 0° C. for 40 minutes, then a solution of1-benzhydryl-azetiin-3-one (0.50 g, 2.1 mmol) in tetrahydrofuran wasintroduced at 0° C. The resulting mixture was refluxed for 2 hours. Thereaction was quenched with water and extracted with methylene chloride(3×50 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum. The crudeoil was column chromatographed on silica gel (20% ethyl acetate-hexane).The product-containing fractions were concentrated under vacuum to give0.29 g (52%) of the title compound as a light yellow solid, m.p. 56-58°C.

[0133] Elemental Analysis for: C₁₈H₁₉NO Calc'd: C, 81.48; H, 7.22; N,5.28. Found: C, 81.03; H, 7.24; N, 5.19.

INTERMEDIATE 26 (1-Benzhydryl-azetidin-3-yl)-acetaldehyde

[0134] A solution of 1-benzhydryl-3-methoxymethylene-azetidine (0.19 g,0.88 mmol) in tetrahydrofuran (20 mL) and 1N hydrogen chloride (10 mL)was refluxed overnight. The mixture was neutralized with saturatedsodium bicarbonate and extracted with methylene chloride (3×50 mL). Thecombined organic extracts were washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to afford0.17 g of the title compound as a light yellow oil. ¹H NMR (400 MHz,DMSO-D₆): δ3.2 (br, 4H), 4.42 (s, 1H), 7.13-7.18 (m, 2H), 7.23-7.27 (m,4H), 7.37-7.40 (m, 4H).

INTERMEDIATE 27 1-[(1-B nzhydryl-az tidin-3-yl)-methoxy-mthyl]-5-fluoro-1H-indol

[0135] A solution of (1-benzhydryl-azetidin-3-yl)-acetaldehyde (0.30 g,1.2 mmol), 5-fluoroindole (0.8 g, 6.0 mmol) and sodium hydroxide (0.06g, 1.6 mmol) in methanol (20 mL) was refluxed for 6 hours. The reactionwas quenched with water and extracted with methylene chloride (3×100mL). The organic layer was washed with water (3×80 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum. The crudeoil was column chromatographed on silica gel (30-40% ethylacetate/hexane). The product-containing fractions were concentratedunder vacuum to give 0.27 g (56%) of the title compound as a lightyellow oil. ¹H NMR (500 MHz, DMSO-D₆): δ2.62 (t, J=6.4 Hz, 1H),2.90-2.95 (m, 2H), 3.02 (t, J=6.1 Hz, 1H), 3.09 (s, 3H), 3.26-3.31 (m,1H), 4.40 (br, 1H), 4.58 (d, J=8.8 Hz, 1H), 6.89 (m, 1H), 7.13-7.18 (m,2H), 7.22-7.27 (m, 4H), 7.31-7.39 (m, 7H), 11.10 (br, 1H).

INTERMEDIATE 281-[(1-Benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole

[0136] This compound was prepared as described for Intermediate 27,using (1-benzhydryl-azetidin-3-yl)-acetaldehyde (0.3 g, 1.2 mmol) andindole (0.7 g, 6.0 mmol), to afford 0.23 g of the title compound as aclear oil. ¹H NMR (500 MHz, DMSO-D₆): δ2.62 (t, J=6.7 Hz, 1H), 2.89 (t,J=7.1 Hz, 1H), 2.98 (m, 1H), 3.03 (t, J=6.7 Hz, 1H), 3.09 (s, 3H), 3.28(t, J=7.1 Hz, 1H), 4.39 (br, 1H), 4.60 (d, J=8.8 Hz, 1H), 6.97 (m, 1H),7.04-7.07 (m, 1H), 7.12-7.17 (m, 2H), 7.22-7.29 (m, 5H), 7.33 (m, 1H),7.37-7.41 (m, 4H), 7.61 (m, 1H), 10.98 (br, 1H).

INTERMEDIATE 293-[(1-Benzhydryl-3-azetidine-3-ylmethyl]-5-fluoro-1H-indole

[0137] A solution of1-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-5-fluoro-1H-indole (0.34g, 0.84 mmol), triethylsilane (2.7 mL, 17 mmol) and trifluoroacetic acid(3.2 mL, 42 mmol) in methylene chloride (20 mL) was refluxed overnight.The reaction was poured into ice and neutralized with concentratedammonium hydroxide. The mixture was extracted with methylene chloride(3×100 mL). The combined organic extracts were washed with water (3×80mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuum. The resulting crude oil was column chromatographed on silica gel(40% ethyl acetate/hexane). The product-containing fractions wereconcentrated under vacuum to give 0.32 g (100%) of the title compound asa clear oil. ¹H NMR (500 MHz, DMSO-D₆): δ2.70-2.78 (m, 3H), 2.88 (d,J=7.1 Hz, 2H), 3,.22 (t, J=7.0 Hz, 2H), 4.40 (br, 1H), 6.86-6.90 (m,1H), 7.15-7.18 (m, 3H), 7.22-7.31 (m, 6H), 7.40-7.42 (m, 4H), 10.85 (br,1H).

INTERMEDIATE 30 3-[(1-Benzhydryl-3-azetidine-3-ylmethyl]-1H-indole

[0138] This compound was prepared as described for Intermediate 29,using 1-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole (1.39 g,3.6 mmol), triethylsilane (11.6 ml, 72 mmol) and trifluoroacetic acid(13.7 mL, 0.18 mol), to afford 0.66 g of the title compound as a lightbrown oil. ¹H NMR (500 MHz, DMSO-D₆): δ2.72-2.79 (m 3H), 2.91 (d, J=7.0Hz, 2H), 3.22 (t, J=6.8 Hz, 2H), 4.39 (br, 1H), 6.95 (m, 1H0, 7.02-7.05(m, 2H0, 7.14-7.17 (m, 2H0, 7.24-7.31 (m, 5H), 7.41-7.42 (m, 4H), 7.48(m 1H), 10.74 (br,1H).

INTERMEDIATE 31 3-Azetidin-3-ylmethyl-5-fluoro-1H-indole

[0139] A mixture of3-[(1-benzhydryl-3-azetidine-3-ylmethyl]-5-fluoro-1H-indole (0.47 g, 1.3mmol), palladium on carbon (10%, 0.1 g) and ammonium formate (0.16 g,2.6 mmol) in ethanol (20 mL) was refluxed for 2 hours. The mixture wasfiltered through celite and the solvent removed under vacuum.Diphenylmethane was removed by triturating the residue with ether,methylene chloride and decanting. The remaining product was dried undervacuum to give 0.19 g of the title compound.

INTERMEDIATE 32 3-Azetidin-3-ylm thyl-1H-indol

[0140] This compound was prepared as described for Intermediate 31,using 3-[(1-benzhydryl-3-azetidine-3-ylmethyl]-1H-indole (0.66 g, 1.9mmol), palladium on carbon (10%, ˜0.1 g) and ammonium formate (0.35 g,5.7 mmol), to afford 0.22 g of the title compound as a off-white solid,m.p. 146-147.5° C. ¹H NMR (500 MHz, DMSO-D₆): δ2.90-2.95 (m, 3H), 3.25(t, J=6.7 Hz, 2H), 3.48 (t, J=7.0 Hz, 2H0, 6.96 (m, 1H), 7.04-7.07 (m,2H), 7.32 (d, J=8.1 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H0, 10.75 (br,1H).

INTERMEDIATE 333-(1-Benzhydryl-azetidin-3-ylmethyl)-5-fluoro-1-methyl-1H-indole

[0141] To a suspension of sodium hydride (60% mineral oil dispersion,0.04 g, 1.0 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added3-azetidin-3-ylmethyl-5-fluoro-1H-indole in DMF at −10° C. The resultingmixture was stirred for 20 min at −10° C., then methyl iodide (0.06 mL,1.0 mmol) was introduced. The mixture was stirred for another 0.5 hourat −10° C. and then quenched with water. The mixture was extracted withmethylene chloride (3×100 mL). The organic layer was washed with water(3×80 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum. The crude oil was column chromatographed onsilica gel (20% ethyl acetate-hexane/hexane). The product-containingfractions were concentrated under vacuum to give 0.32 g of the titlecompound as a clear oil. ¹H NMR (500 MHz, DMSO-D₆): δ2.62-2.73 (m, 3H),2.82 (d, J=7.4 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 3.27 (s, 3H), 4.35 (br,1H), 6.87-6.92 (m, 1H), 7.07-7.13 (m, 3H), 7.130-7.23 (m, 5H), 7.28-7.31(m, 1H), 7.35-7.37 (m, 4H).

INTERMEDIATE 34 3-Azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole

[0142] This compound was prepared as described for Intermediate 31,using 3-(1-benzhydryl-azetidin-3-ylmethyl)-5-fluoro-1-methyl-1H-indole(0.37 g, 0.94 mmol), palladium on carbon (10%, 0.1 g) and ammoniumformate (0.24 g, 2.8 mmol), to afford 0.18 g of the title compound as aclear oil. The oxalate was prepared in ethanol and collected as a whitesolid, m.p. 155-156° C.

[0143] Elemental Analysis for: C₁₃15₄FN₂.C₂H₂O₄ Calc'd: C, 58.38; H,5.55; N, 9.08. Found: C, 58.44; H, 5.45; N, 9.04.

EXAMPLE 12-[3-(5-Fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

[0144] A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.35g, 0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL)was heated at 90° C. under nitrogen overnight. The reaction mixture wasquenched with 1N sodium hydroxide and extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuum. Theresulting crude oil was column chromatographed on silica gel (3%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.090 g of the (S)-enantiomer of thetitle compound as a brown oil. The dihydrochloride salt was prepared inethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C.(dec).

[0145] Elemental Analysis for: C₂₅H₂₄FN₃O₂.2 HCl.3 H₂O Calc'd: C, 55.15;H, 5.92; N, 7.72. Found: C, 55.20; H, 5.73; N, 7.68.

EXAMPLE 22-[3-(5-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-(1,4]dioxino[2,3-f]quinoline

[0146] A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.090g, 0.24 mmol), 5-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.56 g, 0.24mmol) and triethylamine (0.042 mL, 0.36 mmol) in dimethylsulfoxide (10mL) was heated at 90° C. under nitrogen overnight. The reaction mixturewas quenched with 1N sodium hydroxide and extracted with methylenechloride (3×50 mL). The organic layer was washed with water (3×50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated invacuum. The crude oil was column chromatographed on silica gel (5%methanol-75% ethyl acetate-20% hexane). The product-containing fractionswere concentrated in vacuum to give 0.048 g (53%) of the (S)-enantiomerof the title compound as a brown oil. The dihydrochloride salt wasprepared in ethyl acetate and collected as 0.037 g of a yellow solid,m.p. 68° C. (dec).

[0147] Elemental Analysis for: C₂₇H₂₈FN₃O₂.2 HCl.2 H₂O.0.5 EtOAc Calc'd:C, 58.19; H, 6.40; N, 7.02. Found: C, 58.12; H, 6.28; N, 6.90.

EXAMPLE 32-[3-(6-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4dioxino[2,3-f]quinoline

[0148] This compound was prepared as described for Example 2, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.22g, 4.9 mmol), 6-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.13 g, 5.9mmol), to afford 0.11 g (50%) of the (S)-enantiomer of the titlecompound as a light brown oil. The hydrogen chloride salt was preparedin ethyl acetate and collected as 0.12 g of a yellow solid, m.p. 50° C.(dec).

[0149] Elemental Analysis for: C₂₇H₂₈FN₃O₂.2 HCl.3.5 H₂O Calc'd: C,55.77; H, 6.41; N, 7.23. Found: C, 55.46; H, 6.21; N, 6.89.

EXAMPLE 4 2-[3-(1H-Indol-3-ylm thyl)-az tidin-1-ylm thyl]-8-mthyl-2,3-dihydro-[1,4]dioxino]2,3-f]quinoline

[0150] This compound was prepared as described for Example 1, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.26g, 0.59 mmol), 3-azetidin-3-ylmethyl-1H-indole (0.11 g, 0.59 mmol), toafford 0.035 g of the (S)-enantiomer of the title compound as a lightbrown foam. ¹H NMR (500 MHz, DMSO-D₆): δ2.74-2.82 (m, 3H), 2.90 (d,J=7.5 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.03 (t, J=6.6 Hz, 2H), 3.51 (t,J=6.8 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 4.08 (m, 1H), 4.30-4.32 (m, 1H),4.37 (m, 1H), 6.94-6.97 (m, 1H), 7.04-7.08 (m, 2H), 7.30-7.36 (m, 3H),7.42 (d, J=9.1 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H).

EXAMPLE 52-[3-(5-Fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl[-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

[0151] This compound was prepared as described for Example 2, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.24g, 0.53 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole (0.12g, 0.53 mmol), to afford 0.65 g of the (S)-enantiomer of the titlecompound as a light brown oil. The oxalate was prepared in methanol andcollected as 0.047 g of a yellow solid, m.p. 193-195° C.

[0152] Elemental Analysis for: C₂₆H₂₆FN₃O₂.2 C₂H₂O₄.1.25 H₂O Calc'd: C,56.83; H, 5.17; N, 6.63. Found: C, 56.56; H, 4.76; N, 6.52.

INTERMEDIATE 35 6-Fluoro-1-piperidin-4-ylmethyl-1H-indole

[0153] To 6-fluoroindole (1.35 g, 10.0 mmol) in N,N-dimethylformamide(100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.44g, 11 mmol). The mixture was stirred at room temperature under nitrogenfor 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.0 g, 10mmol) added and the mixture heated at 70° C. under nitrogen for 16hours. The solvent was removed in vacuum and replaced with methylenechloride (350 mL). The solution was washed with 250 mL portions of 2Naqueous hydrochloric acid, saturated aqueous sodium bicarbonate andsaturated brine and dried over sodium sulfate. Filtration, concentrationin vacuum and column chromatography on silica gel with methylenechloride as eluent gave 3.7 g of4-(6-fluoro-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester.This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon(0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixturerefluxed under nitrogen for 2 hours. Filtration through celite, followedby concentration in vacuum gave 2.1 g of the title compound as a whitesolid. ¹H-NMR (CDCl₃): doublet of doublets 7.5 δ (1 H); doublet 7.0 δ (1H); doublet of doublets 6.95 δ (1 H); triplet of doublets 6.82 δ (1 H);doublet 6.42 δ (1 H); doublet 3.9 8 (2 H); doublet 3.02 δ (1 H); triplet2.5 δ (2 H); doublet 1.5 δ (2 H); multiplet 1.2 δ (2 H).

EXAMPLE 62-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline

[0154] [(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzene sulfonate (0.90 g, 2.0 mmol) and6-fluoro-1-piperidin-4-ylmethyl-1H-indole (0.70 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanol/chloroform and recrystallization from ethanol with addition offumaric acid gave 0.41 g of the fumarate of the (S)-enantiomer of thetitle compound as a white solid, m.p. 140-142° C.

[0155] Elemental Analysis for: C₂₇H₂₈FN₃O₂.C₄H₄O₄.1.5 H₂O Calc'd: C,63.26; H, 5.99; N, 7.14. Found: C, 63.58; H, 5.84; N, 7.17.

EXAMPLE 72-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl]-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline

[0156] [(2R)-8-Ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-methylbenzene sulfonate (0.50 g, 1.2 mmol) and6-fluoro-1-piperidin-4-ylmethyl-1H-indole (0.70 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanolchloroform and recrystallization from isopropanol with additionof excess HCl gave 0.16 g of the dihydrochloride of the (S)-enantiomerof the title compound as a gold solid, m.p. >250° C.

[0157] Elemental Analysis for: C₂₈H₃₀FN₃O₂.2 HCl.1.5 H₂O Calc'd: C,60.11; H, 6.31; N, 7.51. Found: C, 60.45; H, 6.38; N, 7.15.

INTERMEDIATE 36 1-Piperidin-4-ylmethyl-1H-indole-6-carbonitrile

[0158] To 6-cyanoindole (1.7 g, 12 mmol) in N,N-dimethylformamide (100mL) was added a 60% mineral oil dispersion of sodium hydride (0.48 g, 12mmol). The mixture was stirred at room temperature under nitrogen for 30min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.8 g, 12 mmol)added and the mixture heated at 80° C. under nitrogen for 15 hours. Thesolvent was removed in vacuum and replaced with methylene chloride (400mL). The solution was washed with 350 mL portions of water, saturatedaqueous sodium bicarbonate, and saturated brine and dried over sodiumsulfate. Filtration, concentration in vacuum and column chromatographyon silica gel with methylene chloride as eluent gave 4.4 g of4-(6-cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester.This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon(0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixturerefluxed under nitrogen for 15 hours. Filtration through celite,followed by concentration in vacuum gave 1.9 g of the title compound asa white solid. ¹H-NMR (CDCl₃): doublet 7.6 δ (1 H); singlet 7.55 δ (1H); doublet 7.2 δ (1 H); singlet 7.13 δ (1 H); singlet 6.25 δ (1 H);doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.45 δ (2 H); doublet1.45 δ (2 H); multiplet 1.18 δ (2 H).

EXAMPLE 81-[(1-{[8-Methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)piperidin-4-yl]-1H-indole-6-carbonitrile

[0159] [(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzene sulfonate (0.90 g, 2.0 mmol) and1-piperidin-4-ylmethyl-1H-indole-6-carbonitrile (0.72 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanol/chloroform and recrystallization from ethanol with addition offumaric acid gave 0.40 g of the fumarate of the (S)-enantiomer of thetitle compound as a white solid, m.p. 178-180° C.

[0160] Elemental Analysis for: C₂₈H₂₈N₄O₂.C₄H₄O₄.0.65 H₂O Calc'd: C,66.23; H, 5.78; N, 9.65. Found: C, 65.89; H, 5.66; N, 9.91.

INTERMEDIATE 37 1-(1-Benzhydryl-azetidin-3-lymethyl)-6-fluoro-1H-indole

[0161] To a suspension of sodium hydride (60% mineral oil dispersion,0.19 g, 4.6 mmol) in anhydrous DMF (20 mL) was added 6-fluoroindole(0.65 g, 2.6 mmol) at 0° C. The mixture was stirred at 0° C. for 30minutes, then a solution of methanesulfonic acid1-benzhydryl-azetidine-3-ylmethyl ester (0.78 g, 2.3 mmol) in DMF wasintroduced at 0° C. The resulting mixture heated at 60° C. for 16 hours.The reaction was quenched with water and extracted with methylenechloride (3×50 mL). The organic layer was washed with water (3×50 mL),dried over anhydrous sodium sulfate, filtered and the solvent removedunder vacuum. The crude oil was column chromatographed on silica gel(10-30% ethyl acetate-hexane). The product-containing fractions wereconcentrated under vacuum to give 0.60 g (52%) of the title compound asa light brown oil. MS ES m/e 371 (M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆):2.76-2.79 δ (m, 3H), 3.05-3.07 δ (m, 2H), 4.29-4.31 δ (m, 3H), 6.37 δ(m, 1H), 6.78-6.83 δ (m, 1H), 7.09-7.13 6 (m, 2H), 7.18-7.22 δ (m, 4H),7.31-7.35 δ (m, 6H), 7.46 δ (m, 1 H).

INTERMEDIATE 38 1-Azetidin-3-ylmethyl-6-fluoro-1H-indole

[0162] A mixture of1-(1-benzhydryl-azetidin-3-ylmethyl)-6-fluoro-1H-indole (0.6 g, 1.6mmol), palladium on carbon (10%, catamount) and ammonium formate (0.2 g,3.2 mmol) in ethanol (20 mL) was refluxed for 30 min. The mixture wasfiltered through celite and the solvent removed under vacuum.Diphenylmethane was removed by triturating the residue with ether,methylene chloride and decanting. The remaining product was dried undervacuum. The crude material was directly used in next step withoutfurther purification.

EXAMPLE 92-[3-(6-Fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

[0163] A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.4 g,0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93 mmol)and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml) washeated at 90° C. under nitrogen overnight. The reaction mixture wasquenched with 1N sodium hydroxide and extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuum.The crude oil was column chromatographed on silica gel (3%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.1 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrogen chloride salt was prepared inethyl acetate and collected as a yellow solid: mp: 138° C (dec).

[0164] Elemental Analysis for: C₂₅H₂₄FN₃O₂.2 HCl.2.25 H₂O Calc'd: C,56.56; H, 5.79; N, 7.91. Found: C, 56.59; H, 5.87; N, 7.83.

INTERMEDIATE 393-[2-(6-Fluoro-indol-1-yl)-ethyl]ethyl]-azetidine-1-carboxylic acidtert-butyl ester

[0165] To a suspension of sodium hydride (60% mineral oil dispersion,0.42 g, 10.5 mmol) in anhydrous DMF (40 mL) was added 6-fluoroindole(1.28 g, 5.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30minutes, then a solution of3-[2-(toluene-4-sulfonyloxy)-ethyl]-azetidine-1-carboxylic acidtert-butyl ester (1.51 g, 4.2 mmol) in DMF was introduced at 0° C. Theresulting mixture heated at 60° C. overnight. The reaction was quenchedwith water and extracted with methylene chloride (3×50 mL). The organiclayer was washed with water (3×50 mL), dried over anhydrous sodiumsulfate, filtered and solvent removed under vacuum. The crude oil wascolumn chromatographed on silica gel (20% ethyl acetate-hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.89g (66%) of the title compound as a light brown oil. MS ES m/e 637(2M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆): 1.29 δ (s, 9H), 1.92-1.97 δ (m, 2H),2.33 δ (m, 1 H), 3.3 δ (br, 2H), 3.73 δ (br, 2H), 4.08 δ (t, J=6.9 Hz,2H), 6.39-6.40 δ (m, 1 H), 6.82 δ (m, 1H), 7.32 δ (m, 2H), 7.48 δ (dd,J=5.5, 8.7 Hz, 1H).

INTERMEDIATE 40 1-(2-Azetidin-3-yl-ethyl)-6-fluoro-1H-indole (4)

[0166] A solution of3-[2-(6-fluoro-indol-1-yl)-ethyl]ethyl]-azetidine-1-carboxylic acidtert-butyl ester (43 mg, 0.14 mmol) and ethereal hydrochloric acid (0.27mL, 0.26 mmol) in methanol (10 mL) was refluxed for 2 hours. The solventwas removed under vacuum and the crude oil was washed with saturatedsodium bicarbonate. The mixture was extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuumto give 29 mg of product as a brown oil. The hydrogen chloride salt wasprepared using excess ethereal hydrochloric acid to yield 20 mg of thetitle compound as a yellow solid hydrochloride, m.p. 120-123° C.

[0167] Elemental Analysis for: C₁₃H₁₅FN₂.HCl.0.4 H₂O Calc'd: C, 59.61;H, 6.46; N, 10.69. Found: C, 59.67; H, 6.36; N, 10.59.

EXAMPLE 10 2-{3-[2-(6-Fluoro-indol-1-yl)- thyl]-azetidin-1-ylm thyl}-8-mthyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

[0168] A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.43g, 0.79 mmol), 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g,0.95 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20mL) was heated at 90° C. under nitrogen overnight. The reaction mixturewas quenched with 1N sodium hydroxide and extracted with methylenechloride (3×80 mL). The organic layer was washed with water (3×50 mL),dried over anhydrous sodium sulfate, filtered and the solvent removedunder vacuum. The crude oil was column chromatographed on silica gel(10% methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.3 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrochloride salt was prepared in ethylacetate and collected as a yellow solid: m.p. 115° C. (dec).

[0169] Elemental Analysis for: C₂₆H₂₆FN₃O₂.2 HCl.2 H₂O Calc'd: C, 57.78;H, 5.97; N, 7.77. Found: C, 57.48; H, 5.92; N, 7.60.

EXAMPLE 111-[2-[1-(8-Methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetinin-3-yl]-ethyl}-1H-indole-6-carbonitrile

[0170] A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.21g, 0.45 mmol), 1-(2-azetidin-3-yl-ethyl)-1H-indole-6-carbonitrile (0.11g, 0.52 mmol), which was made in two steps from 6-cyanoindole accordingto the procedures described for Intermediates 40 and 41, andtriethylamine (0.14 ml, 1 mmol) in dimethylsulfoxide (20 ml) was heatedat 90° C. under nitrogen overnight. The reaction mixture was quenchedwith 1N sodium hydroxide and extracted with methylene chloride (3×80ml). The organic layer was washed with water (3×50 ml), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuum.The crude oil was column chromatographed on silica gel (10%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.08 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrochloride salt was prepared in ethylacetate and collected as a yellow solid: yellow solid, m.p. 144° C.(dec).

[0171] Elemental Analysis for: C₂₇H₂₆FN₄O₂.2 HCl.2.5 H₂O Calc'd: C,58.28; H, 5.98; N, 10.07. Found: C, 58.27; H, 5.69; N, 10.00.

INTERMEDIATE 413-[(1-Benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile

[0172] A solution of 1-benzhydryl-3-azetidine-3-carbaldehyde (1.0 g, 4.0mmol), 5-cyanoindole (2.8 g, 20 mmol), and sodium hydroxide (0.19 g, 4.8mmol) in methanol (40 ml) was refluxed for 6 hours. The reaction wasquenched with water and extracted with methylene chloride (3×100 ml).The organic layer was washed with water (3×80 ml), dried over anhydroussodium sulfate, filtered and solvent removed under vacuum. The crude oilwas chromatographed on Biotage (30-40% ethyl acetate-hexane/hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.7g (43%) of the title compound as a light yellow oil. MS ES m/e 406(M−H)⁻; ¹H NMR (500 MHz, DMSO-D₆): 2.42 δ (M, 1H), 2.58 δ (m, 1H), 2.85δ (m, 1 H), 2.91-2.99 δ (m, 2H), 3.05 δ (s, 3H), 4.35 δ (br, 1H), 4.62 6(d, J=8.8 Hz, 1H), 7.07-7.21 δ (m, 5H), 7.23-7.38 6 (m, 6H), 7.47 δ (m,2H), 8.07 δ (m, 1H), 11.54 δ (br, 1H).

INTERMEDIATE 423-(1-Benzhydryl-azetidin-3-ylmethyl)-1H-indole-5-carbonitrile

[0173] A solution of 3-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile,triethylsilane (5.5 ml, 34 mmol) and trifluoroacetic acid (6.6 mL, 86mmol) in methylene chloride (40 mL) was refluxed overnight. The reactionwas poured into ice and neutralized with concentrated ammoniumhydroxide. The mixture was extracted with methylene chloride (3×100 mL).The organic layer was washed with water (3×80 mL), dried over anhydroussodium sulfate, filtered and solvent removed under vacuum. The crude oilwas column chromatographed on a Biotage (40% ethylacetate-hexane/hexane). The product-containing fractions wereconcentrated under vacuum to give 0.56 g (86%) of the title compound asa clear oil. MS ES m/e 378 (M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆): 2.74-2.78δ (M, 3H), 2.96 δ (d, J=6.7 Hz, 2H), 3.21 δ (t, J=6.4 Hz, 2H), 4.4 δ (s,1H), 7.15-7.17 δ (m, 2H), 7.24-7.29 δ (m, 5H), 7.38-7.418 δ (m, 5H),7.47 δ (d, J=8.4 Hz, 1 H), 8.07 δ (s, 1H), 11.37 δ (br, 1H).

INTERMEDIATE 43 3-Azetidin-3-ylmethyl-5-methyl-1H-indole

[0174] A mixture of3-(1-benzhydryi-azetidin-3-ylmethyl)-1H-indole-5-carbonitrile (8) (0.56g, 1.5 mmol), palladium on carbon (10%, 0.1 g) and ammonium formate(0.37 g, 5.9 mmol) in ethanol (20 ml) was refluxed for 2 hours. Themixture was filtered through celite and the solvent removed undervacuum. Diphenylmethane was removed by triturating the residue withether, methylene chloride and decanting. The remaining product was driedunder vacuum. The crude material was directly used in next step. MS ESm/e 200 (M+H)⁺.

EXAMPLE 128-Methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-(1,4]dioxino[2,3-f]quinoline

[0175] This compound was prepared as described for Example 10, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.4 g,0.9 mmol), 3-azetidin-3-ylmethyl-5-methyl-1H-indole (0.19 g, 0.9 mmol),to afford 0.15 g of the (S)-enantiomer of the title compound as a lightbrown oil. The hydrochloride salt was prepared in ethyl acetate andcollected as a yellow solid, m.p. 150° C. (dec).

[0176] Elemental Analysis for: C₂₆H₂₄N₄O₂.2 HCl.2.5 H₂O Calc'd: C,58.76; H, 6.45; N, 7.95. Found: C, 58.82; H, 6.23; N, 7.77.

[0177] When ranges are used herein for physical properties, such asmolecular weight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

[0178] The disclosures of each patent, patent application, andpublication cited or described in this document are herby incorporatedherein by reference, in their entirety.

[0179] Those skilled in the art will appreciate that numerous changesand modifications can be made to the preferred embodiments of theinvention and that such changes and modifications can be made withoutdeparting from the spirit of the invention. It is, therefore, intendedthat the appended claims cover all such equivalent variations as fallwithin the true spirit and scope of the invention.

What is claimed is:
 1. A compound of Formula I:

wherein Q is

R¹, R² and R³ are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms; X and Y are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, alkanesulfonyl of 1 to 6 carbon atoms or alkanesulfonamido of 1 to 6 carbon atoms, or X and Y, taken together, form —N═C(R⁴)—C(R⁵)═N—, —N═C(R⁴)—C(R⁶)═CH—, —N═C(R⁴)—N═CH—, —N═C(R⁴)—O—, —NH—C(R⁷)═N— or —NH—C(R⁸)═CH—; R⁴ and R⁵ are, independently, hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁷ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or alkyl of 1 to 6 carbon atoms; Z is O, S, or NR⁹, in which R⁹ is hydrogen or alkyl of 1 to 6 carbon atoms; n is an integer 0, 1, or 2; m is an integer from 1 to 4, provided that m+n≦4 and that when m=n=2, and Q is b then X and Y are not NH—C(R8)═CH—; and p is an integer from 1 to 3, provided that p+n is 2 or 3; or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1, wherein X and Y, taken together, form —N═C(R⁴)—C(R⁶)═CH— or a pharmaceutically acceptable salt thereof.
 3. A compound according to claim 1, wherein Q is

or a pharmaceutically acceptable salt thereof.
 4. A compound according to claim 1, wherein Z is NR⁹ or a pharmaceutically acceptable salt thereof.
 5. A compound according to claim 1, wherein n is 0 or 1 or a pharmaceutically acceptable salt thereof.
 6. A compound according to claim 1, wherein m is 1 to 3 or a pharmaceutically acceptable salt thereof.
 7. A compound according to claim 1, wherein p is 1 or 2 or a pharmaceutically acceptable salt thereof.
 8. A compound according to claim 1, wherein R¹ is hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof.
 9. A compound according to claim 1, wherein R² and R³are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof.
 10. A compound according to claim 1, wherein R⁴ and R⁵ are independently hydrogen, amino or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof.
 11. A compound according to claim 1, wherein R⁷ and R⁸ are independently selected from hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof.
 12. A compound according to claim 1, wherein R⁶ is hydrogen or alkyl of 1 to 3 carbon atoms, Z is NR⁹ in which R⁹ is hydrogen or alkyl of 1 to 3 carbon atoms, n is 0 or 1, m is 1 to 3 and p is 1 or 2 or a pharmaceutically acceptable salt thereof.
 13. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.
 14. A compound according to claim 1, wherein said compound is 2-[3-(5-fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 15. A compound according to claim 1, wherein said compound is 2-[3-(5-fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 16. A compound according to claim 1, wherein said compound is 2-[3-(6-fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 17. A compound according to claim 1, wherein said compound is 2-[3-(1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 18. A compound according to claim 1, wherein said compound is 2-[3-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 19. A compound according to claim 1, wherein said compound is 2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 20. A compound according to claim 1, wherein said compound is 2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 21. A compound according to claim 1, wherein said compound is 1-[(1-{[8-Methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)piperidin-4-yl]-1H-indole-6-carbonitrile or a pharmaceutically acceptable salt thereof.
 22. A compound according to claim 1, wherein said compound is 2-[3-(6-Fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinoline or a pharmaceutically acceptable salt thereof.
 23. A compound according to claim 1, wherein said compound is 2-{3-[2-(6-Fluoro-indol-1-yl)-ethyl]-azetidin-1-ylmethyl}-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 24. A compound according to claim 1, wherein said compound is 1-{2-[1-(8-Methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetinin-3-yl]-ethyl}-1H-indole-6-carbonitrile or a pharmaceutically acceptable salt thereof.
 25. A compound according to claim 1, wherein said compound is 8-Methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline or a pharmaceutically acceptable salt thereof.
 26. A compound according to claim 1, wherein said compound is the S enantiomer at the 2-aminomethyl-2,3-dihydro-1,4-benzodioxan moiety, substantially free of the R enantiomer of said compound.
 27. A method of treating a subject suffering from a condition selected from depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol addiction, and sexual dysfunction, comprising the step of: administering to said subject suffering from said condition a therapeutically effective amount of a compound according to claim
 1. 28. A method according to claim 27, wherein the condition is depression.
 29. A method according to claim 27, wherein the condition is selected from the group consisting of obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, and social anxiety disorder.
 30. A pharmaceutical composition, comprising: an effective amount of a compound according to claim 1; and a pharmaceutically acceptable carrier or excipient. 